Ignite Creation Date:
2024-05-06 @ 10:33 AM
Last Modification Date:
2024-10-26 @ 12:31 PM
Study NCT ID:
NCT03282656
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2024-07-09
First Post:
2017-08-22
Brief Title:
Gene Transfer for Sickle Cell Disease
Sponsor:
David Williams
Organization:
Boston Childrens Hospital
Study Overview
Official Title:
Pilot and Feasibility Study of Hematopoietic Stem Cell Gene Transfer for Sickle Cell Disease
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2024-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
A promising approach for the treatment of genetic diseases is called gene therapy Gene therapy is a relatively new field of medicine that uses genetic material mostly DNA from the patient to treat his or her own disease In gene therapy the investigators introduce new genetic material in order to fix or replace the patients disease gene with the goal of curing the disease The procedure is similar to a bone marrow transplant in that the patients malfunctioning blood stem cells are reduced or eliminated using chemotherapy but it is different because instead of using a different persons donor blood stem cells for the transplant the patients own blood stem cells are given back after the new genetic material has been introduced into those cells This approach has the advantage of eliminating any risk of GVHD reducing the risk of graft rejection and may also allow less chemotherapy to be utilized for the conditioning portion of the transplant procedure The method used to introduce the gene into the patients own blood stem cells is to engineer and use a modified version of a virus called a vector that efficiently inserts the correcting genetic material into the cells The vector is a specialized biological medicine that has been formulated for use in human beings
The investigators have recently discovered a gene that is very important in the control of fetal hemoglobin expression Increasing the expression of this gene in sickle cell patients could increase the amount of fetal hemoglobin while simultaneously reducing the amount of sickle hemoglobin in their blood and therefore potentially cure the condition In summary the advantages of a gene therapy approach include 1 it can be used even if the patient does not have a matched donor available 2 it may allow a reduction in the amount of chemotherapy required to prepare the patient for the transplant and 3 it will avoid the strong medicines often required to prevent and treat GVHD and rejection The goal is to test whether this approach is safe and whether using gene therapy to change the expression of this particular gene will lead to increased fetal hemoglobin production in people with sickle cell disease
The investigators have recently discovered a gene that is very important in the control of fetal hemoglobin expression Increasing the expression of this gene in sickle cell patients could increase the amount of fetal hemoglobin while simultaneously reducing the amount of sickle hemoglobin in their blood and therefore potentially cure the condition In summary the advantages of a gene therapy approach include 1 it can be used even if the patient does not have a matched donor available 2 it may allow a reduction in the amount of chemotherapy required to prepare the patient for the transplant and 3 it will avoid the strong medicines often required to prevent and treat GVHD and rejection The goal is to test whether this approach is safe and whether using gene therapy to change the expression of this particular gene will lead to increased fetal hemoglobin production in people with sickle cell disease
Detailed Description:
This is an open-label non-randomized single center pilot and feasibility single arm cohort study involving a single infusion of autologous bone marrow derived CD34 HSC cells transduced with the lentiviral vector containing a short-hairpin RNA targeting BCL11a Accrual will be a maximum of 7 evaluable patients with SCD The study will have three strata
1 Stratum 1 ages 18-40
2 Stratum 2 ages 12-18
3 Stratum 3 ages 3-12
To determine the feasibility and safety of administering a lentiviral gene transfer vector encoding a small hairpin sh RNA targeting the γ-globin gene repressor BCL11A in patients with severe SCD
Patients will undergo standard work-up for autologous bone marrow transplantation according to institutional guidelines and then undergo two bone marrow harvests at a minimum of 4 weeks apart that will be used for a back-up marrow minimum of 2 x 106 CD34 cellskg and for a harvest of autologous bone marrow for gene transfer
Patients will receive blood transfusions for a period of 3 months prior to the planned date of product infusion with a goal of achieving a HbS level 30 by the time of gene transfer If the subject is already on a chronic transfusion regimen as part of baseline disease management the regimen may be continued The timing of transfusions will be coordinated to occur within 7 days prior to any procedures requiring anesthesia such as bone marrow harvest
Hematopoietic cells will be collected from the patient in advance of the treatment to serve as a salvage procedure back-up graft should there be no hematopoietic recovery observed following the injection of genetically-manipulated cells or should manipulated cells fail to meet release criteria Bone marrow up to 20 mLkg will be harvested from the patient under general anesthesia from the posterior iliac crests on both sides by multiple punctures at a minimum of 4 weeks prior to gene therapy A portion of the bone marrow containing at least 2 x 106 CD34 cellskg will be frozen and stored unmanipulated according to standard clinical procedures for autologous bone marrow collection to constitute the back-up graft If the number of CD34 cells that exceeds 2 x 106 cellskg is greater than or equal to 1 x 106 cellskg these excess cells would be processed for transduction transduced and then frozen Transduction will be carried out on the selected CD34 cells and transduced cells will be cryopreserved If cells from the first harvest were transduced and frozen these gene-modified cells will be thawed and prepared for infusion in parallel with the product from the subsequent harvests In this case two separate products would be infused All cell manipulation procedures and release testing will be performed in the transduction facility in accordance with Good Manufacturing Practice GMP following process specific standard operating procedures Final Drug Product will be accompanied by a Certificate of Analysis documenting that all release testing is complete and within specification Subjects will receive myeloablative conditioning with Busulfan administered on days -5 to -2 prior to infusion of transduced cells Cells will be infused intravenously over 30-45 minutes after standard prehydration and premedication according to Boston Childrens Hospital Hematopoietic Stem Cell Transplantation Unit standard guidelines This standard requires that the patient be on continuous cardiac respiratory and oxygen saturation monitor throughout the infusion and for 30 minutes afterwards Vital signs will be measured and recorded pre-transfusion 15 minutes into transfusion every hour for duration of infusion and end of transfusion The RN will stay with the patient for the first 5 minutes of the transfusion If two transduction products are administered the second transduced product will be administered without delay after the first
1 Stratum 1 ages 18-40
2 Stratum 2 ages 12-18
3 Stratum 3 ages 3-12
To determine the feasibility and safety of administering a lentiviral gene transfer vector encoding a small hairpin sh RNA targeting the γ-globin gene repressor BCL11A in patients with severe SCD
Patients will undergo standard work-up for autologous bone marrow transplantation according to institutional guidelines and then undergo two bone marrow harvests at a minimum of 4 weeks apart that will be used for a back-up marrow minimum of 2 x 106 CD34 cellskg and for a harvest of autologous bone marrow for gene transfer
Patients will receive blood transfusions for a period of 3 months prior to the planned date of product infusion with a goal of achieving a HbS level 30 by the time of gene transfer If the subject is already on a chronic transfusion regimen as part of baseline disease management the regimen may be continued The timing of transfusions will be coordinated to occur within 7 days prior to any procedures requiring anesthesia such as bone marrow harvest
Hematopoietic cells will be collected from the patient in advance of the treatment to serve as a salvage procedure back-up graft should there be no hematopoietic recovery observed following the injection of genetically-manipulated cells or should manipulated cells fail to meet release criteria Bone marrow up to 20 mLkg will be harvested from the patient under general anesthesia from the posterior iliac crests on both sides by multiple punctures at a minimum of 4 weeks prior to gene therapy A portion of the bone marrow containing at least 2 x 106 CD34 cellskg will be frozen and stored unmanipulated according to standard clinical procedures for autologous bone marrow collection to constitute the back-up graft If the number of CD34 cells that exceeds 2 x 106 cellskg is greater than or equal to 1 x 106 cellskg these excess cells would be processed for transduction transduced and then frozen Transduction will be carried out on the selected CD34 cells and transduced cells will be cryopreserved If cells from the first harvest were transduced and frozen these gene-modified cells will be thawed and prepared for infusion in parallel with the product from the subsequent harvests In this case two separate products would be infused All cell manipulation procedures and release testing will be performed in the transduction facility in accordance with Good Manufacturing Practice GMP following process specific standard operating procedures Final Drug Product will be accompanied by a Certificate of Analysis documenting that all release testing is complete and within specification Subjects will receive myeloablative conditioning with Busulfan administered on days -5 to -2 prior to infusion of transduced cells Cells will be infused intravenously over 30-45 minutes after standard prehydration and premedication according to Boston Childrens Hospital Hematopoietic Stem Cell Transplantation Unit standard guidelines This standard requires that the patient be on continuous cardiac respiratory and oxygen saturation monitor throughout the infusion and for 30 minutes afterwards Vital signs will be measured and recorded pre-transfusion 15 minutes into transfusion every hour for duration of infusion and end of transfusion The RN will stay with the patient for the first 5 minutes of the transfusion If two transduction products are administered the second transduced product will be administered without delay after the first
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None